Controlled flow instrument for microwave assisted chemistry with high viscosity liquids and heterogeneous mixtures

ABSTRACT

A controlled-flow microwave instrument for chemical synthesis using heterogeneous or highly viscous starting materials includes a microwave source for generating electromagnetic radiation in the microwave frequencies, a microwave cavity in wave communication with the source for exposing compositions placed therein to microwave radiation, a microwave-transparent pressure resistant reaction vessel in the cavity, a source reservoir for starting materials and related compositions, a pump in communication with the source reservoir for pumping heterogeneous or highly viscous materials from the source reservoir to the reaction vessel, and a pressure-resistant valve between the pump and the reaction vessel for isolating the reaction vessel from the pump and the source reservoir during application of microwave energy to compositions in the vessel and from any resulting high pressures generated therein.

This is a continuation of copending application Ser. No. 10/605,021filed Sep. 2, 2003.

BACKGROUND

The present invention relates to microwave-assisted chemical processesand in particular relates to microwave-assisted chemical synthesis,carried out in automated, controlled-flow fashion, using heterogeneousand high-viscosity compositions and while providing for high pressurereactions.

The use of microwaves to provide energy to initiate, drive or controlchemical reactions is well-established. Although conceptually,microwaves can be used to affect a wide variety of chemical reactions,the commercial use of microwave assisted chemistry initially grew mostrapidly in techniques such as loss-on-drying (gravimetric) moistureanalysis and digestion reactions that provided the foundation forcontent analysis. Indeed, such reactions still represent a major part ofthe instrument market for microwave assisted chemistry. In particular,gravimetric analysis and digestion can often be carried out in ratherrobust fashion, for which the longer wavelengths and broad controlparameters of microwaves are well-suited.

More recently, interest has greatly increased in using microwaves todrive more sensitive reactions, particularly organic synthesis, and todo so on the smaller scale—and thus more highly controlled basis—that ispreferred (or necessary) in many research oriented applications. Boththe speed and nature of microwaves offer certain advantages. Becausemicrowaves react immediately with polar and semi-polar materials, theyhelp avoid the lag time inherent in other forms of energy transfer suchas conduction or convection heating. Thus, they offer a time advantagefor many research schemes including those broadly referred to as“combinatorial chemistry.” Just as importantly, however, electromagneticradiation in the microwave frequencies can affect individual molecules(and thus compositions) somewhat differently—and thus potentially morefavorably—than convention or conduction heating. Some of theseadvantages are explained in more detail in Hayes, MicrowaveSynthesis-Chemistry at the Speed of Light, 2002 CEM Publishing (ISBN0-9722229-0-1).

As an additional factor, single mode cavity microwave instruments havebecome commercially available that are well-suited for controlledapplication of microwave radiation to small samples. These include theVOYAGER®, DISCOVER® and EXPLORER® instruments available from CEMCorporation, Matthews, N.C., for which more formal descriptions are setforth (but not limited to) U.S. Published Patent Applications Nos.20030089706 and 20020117498, U.S. Pat. Nos. 6,867,400; 6,744,024;6,607,920; and 6,521,876, and pending unpublished application Ser. Nos.10/249,011 filed Mar. 10, 2003 and Ser. No. 10/126,838 filed Apr. 19,2002. The contents of all of these are incorporated entirely herein byreference.

Several of these devices are batch-type devices; i.e. microwaves areapplied to a fixed sample in a closed reaction vessel (or a set of fixedsamples in several respective separate vessels. When an additionalreaction is to be carried out, a new set of starting materials areplaced in a new reaction cell which is placed in turn in the microwavecavity. Although the use of individual vessels can be automated, for themost part the reactions must be carried out in batch fashion.

For some commercial applications, however, a constant or continuousreaction scheme—i.e. exposing a continuous stream of reactants to themicrowaves and producing a continuous stream of product, withoutintermittent manipulation of a series of vessels—is attractive ornecessary option. The present generation of instrument suitable for thistype of reaction is exemplified by CEM's VOYAGER® instrument (e.g. U.S.Pat. No. 6,867,400). This type of instrument is broadly exemplified byan appropriate source of liquid starting materials, suitable fluid pumps(with those for high pressure liquid chromatography, “HPLC” beingexemplary), and a flow path that carries the reactants through amicrowave field for a time sufficient for a desired reaction to takeplace. The time spent in the microwave field is, however, dictated bythe diameter and length of the flow path taken together with the flowrate of the reactants. Because practical considerations tend to limitthe length of the flow path that can be conveniently placed in acommercial instrument, the time spent in the microwave field is alsolimited.

Although the latest generation of both the batch and continuous systemsoffer significant advantages for chemical synthesis, each includescharacteristics that preclude it from handling certain types ofreactions. The batch systems can handle high pressure and heterogeneousstarting materials, but cannot offer continuous operation from areactant source. The flow-through systems can use reactants and generateproducts on a continuous basis, but generally cannot handle (because ofpumping or flow considerations) heterogeneous starting materials or highviscosity fluids, or do so at high pressures. For example, conventionalHPLC pumps cannot handle higher viscosity liquids or any solidswhatsoever. Even if pumps that can handle solids are incorporated,however, the available flow rates raise specific problems in microwaveassisted chemistry. Higher flow rates help move solids through theinstrument but reduce the available time spent in the microwave field.Lower flow rates will (mathematically at least) increase residence timein the microwave field, but tend to encourage heterogeneous mixtures(typically liquid reactants and solvents in combination with solid-phasecatalysts or solid-supported reagents) to separate into their respectivephases before reacting properly or, in severe cases, blocking the flowpath and rendering the instrument temporarily or permanently unusable.

Flow-through devices also lack a stirring capability, which can beparticularly important for heterogeneous mixtures. Furthermore, precisetemperature control (as opposed to consistent application of microwaveradiation) is different or impossible in flow-through systems.Additionally, many prior flow-through systems require multimode cavitiesor otherwise operate in multimode fashion. Finally, conventionalflow-through systems can often handle homogeneous liquids at highpressure or heterogeneous mixtures at low pressures, but cannot providea continuous flow reaction system for carrying out high pressurereactions on heterogeneous materials. Because higher pressures (e.g. upto 250 psi or more) are advantageous to or necessary for certainreaction schemes, the ability to carry them out on an automated or flowthrough basis presents a function disadvantage.

Prior descriptions of proposed (or actual) flow-though or continuousdevices tend to reflect—even if by silence—these limitations.

For example, U.S. Pat. No. 5,387,397 to Strauss discloses a flow-throughmicrowave instrument that can nominally provide “a continuous andpressurized feed of liquid or slurry to and through a microwave heatingzone” (column 2, lines 46-47). Of the approximately 27 actual examplesincluded in the '397 patent, however, only two refer explicitly to theuse of a heterogeneous mixture. In particular, the preparation of4-(1-cyclohex-1-enyl) morpholine at column 11, line 62 uses a finelyground starting material in a solvent, and the preparation of phenylvinyl ketone at column 12 line 16 describes a suspension of 5 grams ofstarting material in 400 milliliters of water. Other examples may createheterogeneous mixtures, but if so, Strauss does not appear to focus uponthem.

Stated differently, the heterogeneous mixtures described by Strauss arein the neighborhood of about one percent by weight of the otherwiseliquid volume being pumped. Furthermore, although Strauss refers topressure control, it is in the nature of a continuous flow system anddoes not provide for extended residence times.

Katschnig No. 5,403,564 describes a microwave system for thermaldecontamination of “pumpable or pourable” material, but essentiallyoperates at between about one and two atmospheres.

Knapp No. 5,672,316 describes a flow-through system in which higherpressure is equilibrated by placing a flow path within apressure-containing vessel while leaving one end of the flow path opento the interior of the vessel and a reservoir of liquid in the vessel tothereby cause the pressure on the inside and the outside of the flowpath to be identical.

Haswell No. 5,215,715, which is commonly assigned with the presentinvention, describes a flow-through system in which samples to bedigested are moved through a microwave cavity as discreet slugs atpressures of between about 30 and 120 pounds per square inch (PSI). TheHaswell instrument is primarily for digestion rather than chemicalsynthesis as indicated by the nature of the flow-through system and themanner in which the slug and solvent are pumped through it.

Renoe No. 5,420,039, which is also commonly assigned with the presentinvention, describes a flow-through system in which water is pumpedthrough at high pressure, but an ordinary sample is carried by the waterrather than being pressurized. In particular, pressure is controlled inthe 039 patent for the purpose of keeping gasses dissolved in a liquidsample so that the liquid sample can be consistently evaluated using acapacitance detection system.

Accordingly, in spite of the advantages and designs formicrowave-assisted instruments, there remains a need for an instrumentthat can operate in automated, semi-continuous fashion, that can handlehighly viscous liquids and heterogeneous mixtures, can do so at highpressure, and with microwave assistance.

SUMMARY

The invention is a controlled-flow microwave instrument for chemicalsynthesis that includes (or generates) heterogeneous or highly viscousmaterials, including starting materials. The instrument includes amicrowave source for generating electromagnetic radiation in themicrowave frequencies, a microwave cavity in wave communication with thesource for exposing compositions placed in the cavity to microwaveradiation, a microwave-transparent pressure resistant reaction vessel inthe cavity, a source reservoir for starting materials and relatedcompositions, a pump in communication with the source reservoir forpumping heterogeneous or highly viscous materials from the source to thereaction vessel, and a pressure-resistant valve between the pump and thereaction vessel for isolating the reaction vessel from the pump and thesource during application of microwave energy to compositions in thevessel and from any resulting high pressures generated therein.

The foregoing and other objects and advantages of the invention and themanner in which the same are accomplished will become clearer based onthe followed detailed description taken in conjunction with theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of an instrument according to the claimedinvention.

FIG. 2 is a perspective view of an instrument according to the claimedinvention.

FIG. 3 is another perspective view of an enlarged portion of FIG. 2.

DETAILED DESCRIPTION

FIG. 1 is a schematic diagram of a controlled-flow microwave instrumentfor chemical synthesis using heterogeneous or highly viscous startingmaterials. The instrument comprises a microwave source designated at 10for generating electromagnetic radiation in the microwave frequencies. Amicrowave cavity 11 is in wave communication with the source 10 forexposing compositions placed therein to microwave radiation. Asillustrated in FIG. 1, the cavity 11 and the source 10 communicatethrough a waveguide 12. In preferred embodiments, the microwave cavity10 is a single or dual mode cavity. Single and dual mode cavities arepreferred because the value of the microwave field is predetermined atparticular positions in the cavity on a consistent and reproduciblebasis.

A microwave transparent pressure resistant reaction vessel 13 ispositioned (partially or entirely) within the cavity 11. Although it issufficient for a portion of the vessel 13 to be transparent to microwaveradiation, in preferred embodiments, the entire reaction vessel istransparent with the possible exception of an appropriate pressurefitting or cap illustrated at 14 in FIG. 1. The most preferred materialsfor the reaction vessel 13 are typically quartz, glass, or engineeringplastics. In the preferred embodiments, the pressure resistant reactionvessel 13 has sufficient strength to maintain reactions therein atpressures of at least about 175 lbs. per square inch (psi). In the mostpreferred embodiments, the pressure-resistant reaction vessel 13 hasstrength sufficient to maintain pressures of at least about 250 lbs. persquare inch, as well as all incremental pressures between 175 and 250psi. There is, of course, no upper limit to the pressures that can beused in the vessel or the instrument other than the limits of thefunctional items such as the pressure vessel, the valves, and the pump.The indicated pressure range of 175-250 psi is, however, a range that isparticularly useful for carrying out a wide variety of organic synthesisreactions, and thus is exemplary of the capabilities of the invention.

FIG. 1 illustrates two source reservoirs 15 and 16 for startingmaterials and related compositions such as catalysts, solvents andsolid-supported reagents. For some starting materials and reactions,only one source reservoir is required, but more can be accommodated byincluding additional valves and piping as may be desired or necessary tocarry out particular reactions or reaction schemes. The reservoirs 15and 16 communicate with other portions of the instrument through therespective fluid lines 21 and 29. The term “reservoir” is used in abroad sense herein and does not necessarily refer to a particular typeof container or vessel. Instead, the term can apply to any source ofstarting material, solvent, catalyst or any other composition that maybe used in the reaction and pumped through the instrument in the mannerdescribed herein.

A pump 17, preferably a peristaltic pump, is in communication with thesource reservoir 15 for pumping heterogeneous or highly viscousmaterials from the source 15 to the reaction vessel 13 through variousfluid lines, two of which are designated at 22 and 28. Peristaltic pumpsare generally well-understood in this (and other arts) and arecommercially available from a wide variety of sources and will not beotherwise described in detail herein.

Although a peristaltic pump is preferred, other types of pumps can beused if desired or necessary with typical examples being diaphragm pumpsor pneumatic pumps. These are likewise well understood in the art andwill not be described in detail herein. Any pump is appropriate providedthat it carries out its pumping function in accordance with theremainder of the operation of the instrument.

FIG. 1 also illustrates that the instrument comprises a temperaturedetector illustrated at 24 associated with the cavity 11 for measuringthe temperature of the vessel 13 or its contents. In such embodiments,the instrument also comprises means for adjusting the microwave powerapplied from the source 10 to the cavity 11. In FIG. 1, the adjustingmeans is illustrated at 27 and can comprise (for example) a switchingpower supplying as set forth in commonly assigned U.S. Pat. No.6,288,379, or an optical lens system as set forth in commonly assignedU.S. Pat. No. 5,796,080. The switching power supply moderates theapplied microwaves by moderating the power supplied to the source 10.The lens system moderates the microwaves after they are generated and asthey are propagated into the waveguide 12 and then into the cavity 11.

FIG. 1 illustrates that the instrument most preferably includes aprocessor illustrated at 26 in operative communication with thetemperature detector 24 and the adjusting means 27 for adjusting themicrowaves applied from the source 10 to the cavity 11 in response tothe temperature measured by the detector 24. In preferred embodiments,the temperature detector 24 is an infrared optical detector whichmeasures the wavelength of infrared radiation produced by the vessel 13or its contents and converts this into an electrical signal which iscarried by signal line 25 to the processor 26. In this manner, thetemperature detector can be used to help moderate, control, or maintaina constant temperature within the cavity 11 or for the vessel 13 or itscontents as may be desired or necessary for some or all portions of achemical reaction scheme.

The instrument also preferably comprises means shown as the fan 30 forcooling the vessel (and thus its contents) in the cavity at any time,but particularly during the application of microwaves. As schematicallyillustrated in FIG. 1, the fan 30 includes an air intake 31 and anoutput 32 for directing a flow of cooling air into the cavity 11. Othercooling fluids can also be used, including an inert gas maintained at adesired low-temperature. The use of temperature control in organicsynthesis reactions in connection with microwave assisted chemistry isset forth in commonly assigned U.S. Pat. No. 6,744,024, the contents ofwhich are incorporated entirely herein by reference. As set forththerein, by controlling the temperature of a reaction while concurrentlyadding microwave radiation, the microwave radiation can drive or controlthe reaction in a desired manner, while keeping the vessel's contentsbelow a temperature that would allow the reaction to proceed in anundesired manner or potentially decompose sensitive reactants orproducts.

In other circumstances, the reaction of interest may not need to becooled during the application of microwaves, but the cooling functioncan be carried out after the reaction is complete for the purpose ofcooling the vessel and its contents and reducing the internal pressureprior to opening the vessel in the manner described later herein. Stateddifferently, the instrument has the capability of cooling the cavity,the vessel and the vessel's contents at any time, but the ability to doso during the application of microwave radiation is particularly usefulin carrying out certain reactions.

As illustrated in FIG. 1, the fan 30 is in operative communicationthrough the signal line 33 with the processor 26 to thereby operate thefan 30 in response to the temperature measured by the temperaturedetector.

In preferred embodiments, the microwave source 10 is selected from thegroup consisting of magnetrons, klystrons, and solid-state devices.Magnatrons are often commercially preferred because of theirwell-understood operation, wide availability, moderate size, andappropriate cost. These tend to be commercial factors, however, and arenot limiting of the scope of the invention.

As noted in the background, the characteristic problem with respect tomicrowave-assisted chemistry of heterogeneous mixtures is that such cantypically be pumped at low pressures. Alternatively, heterogeneousreactions can be carried out at high pressures, but cannot be pumped athigh pressures. Accordingly, in order to address these complimentaryproblems, the instrument includes a pressure resistant valve designatedat 34 in FIG. 1. The pressure-resistant valve 34 is positioned betweenthe peristaltic pump 17 and the reaction vessel 13 for isolating thereaction vessel 13 from the pump 17 and from the source 15 duringapplication of microwave energy to compositions in the vessel 13 and forisolating the reaction vessel from the lower pressure portions of theinstrument when high pressures are generated in the reaction vessel 13as a result of the chemical reactions being carried out therein. Inpreferred embodiments, the pressure resistant valve comprises a ballvalve that is pressure resistant to at least about 175 psi andpreferably to at least about 250 psi, and to all pressure incrementstherebetween. In most circumstances, the pressure resistance of thevalve 34 should at least match, and preferably exceed, that of thereaction vessel 13.

The valve 34 communicates with the vessel 13 through at least one fluidline illustrated at 28 in FIG. 1. As shown therein, the fluid line 28preferably extends to a point near the bottom of the vessel 13 to thuspermit materials to be delivered to, and more importantly pumped from,the bottom portions of the vessel 13. A gas line (23 in FIG. 1) ispositioned in upper portions of the vessel 13 in order to best deliveran inert gas to the vessel to help push materials from the vessel afterchemical reactions therein are completed.

The various fluid lines used in the instrument can be selected as may bedesired or necessary for various purposes. Typically, the lines areformed of materials that are chemically inert to the materials beingtransferred therethrough and mechanically strong enough to withstand thedesired or necessary pressures. Thus, glass, metal and polymers are allsatisfactory candidate materials, with various fluorinated hydrocarbonpolymers (e.g., polytetrafluoroethylene and related polymers) beingparticularly suitable. The lines 23, 28 between the ball valve 34 andthe vessel 13 should, of course, be strong enough to withstand theexpected high pressures generated by reactions in the vessel 13 andnecessarily maintained between the vessel 13 and the ball valve 34.

In the more preferred embodiments, the peristaltic pump 17 is a two-waypump for adding materials to and pumping materials from the reactionvessel 13. In such embodiment, the instrument further comprises amulti-port valve broadly designated at 36 and positioned between thesource reservoirs 15, 16 and the peristaltic pump 17 for controlling theflow of materials to and from the reaction vessel 13. Fluid line 20connects the multi-port valve 36 to the pump 17. The multi-port(multi-function, multi-position) valve 36 is also in fluid communicationwith a product reservoir 37 through fluid line 40. In the most preferredembodiments, the multi-port valve 36 is also in communication with aprocessor (preferably the common processor 26), that is also inoperative communication with the peristaltic pump 17 and the valve 36,for directing the flow of materials to and from the multi-port valve 36,the two-way pump 17, and the reaction cell 13. FIG. 1 illustrates thatthe valve 36 is in signal communication with the processor 26 throughthe signal line 41, and that the processor 26 is in communication withthe peristaltic pump 17 through the signal line 42.

FIG. 1 also illustrates a plurality of fluid lines, some of which havealready been designated with reference numerals, for providing the fluidcommunication described herein within the instrument. Thus, inconjunction with the fluid lines, the instrument further comprises asolvent supply 43 that connects to the valve 36 through the fluid line44 for providing solvent to the reaction cell, or for rinsing andcleaning the various fluid lines, or both. A vent 45 is also in fluidcommunication with the multi-port valve 36 through fluid lines 46, gate(or equivalent) valve 47, and fluid lines 50 and 51. A waste reservoir52 is also in fluid communication with the multi-port valve 36 throughthe fluid line 53 for receiving waste product, for example after rinsing(“backwashing”).

In preferred embodiments, some of the fluid transfer, particularly forrinsing and backwashing, is carried out using an inert (i.e. chemicallyinert to the instruments and the reactions and the materials in thereactions) from a gas supply 54, which also communicates with the valve36 through the fluid line 51. Depending upon the positions of themulti-port valve 36, the ball valve 34, the gate valve 47, a second gatevalve 55, pressurized gas from the supply 54 can be used to push solventthrough the respective lines in one or opposite directions as desired ornecessary. Depending upon the orientation of the various valves, gasfrom the supply 54 can also be added to the vessel 13, either as areactant or as an inert gas to help pump materials from the vessel 13.

The instrument also optionally includes a fluid level detector 38 thatadds additional automated features to the instrument. In particular, oneor two fluid level detectors 38 can be included, with only oneillustrated in FIG. 1. When a single detector is used, it will detectthe start (“head”) of fluid flow from one of the reservoirs of 15, 16toward the vessel 13. It can also detect the end of the flow (tail) andthus confirm that an appropriate amount of liquid has been added to thevessel. Because the processor 26 is programmed to know or select theamount of liquid being added to the vessel 13, the time period thatextends between the head of the liquid flowing past the detector 38 andthe tail of the liquid flowing past the detector 38 should correspond tothe amount of liquid being sent to the vessel 13. If this differs fromthe amount calculated or desired by the processor, the instrument can beshut down until an operator can make the appropriate corrections oradjustments.

When two detectors are used, the detection of the head or tail of thefluid flow from one of the detectors to the next can also be used tocalculate a flow rate which can be useful or necessary in a number ofcircumstances.

The lines and fixtures required to move solvent and gas in this mannerare well understood in this art, and the flow paths indicated in FIG. 1for this purpose are exemplary rather than limiting, and will not bedescribed in further detail herein.

FIG. 2 is a perspective view of a commercial embodiment of theinstrument shown schematically in FIG. 1. In FIG. 2 the instrument isbroadly designated at 9, and includes a lower housing 18 and an upperhousing 19. The cavity 11 is within the lower housing 18 and itslocation is broadly designated at 11. As described earlier, in preferredembodiments the portion of the instrument 9 that is included in thelower housing 18 is substantially identical to CEM's DISCOVER™instrument which is described on CEM's web site (www.cem.com) and setforth in several of the previously-incorporated patents andapplications.

Portions of the vessel 13 are positioned in the cavity 11 and the vessel13 includes a pressure lid or cap 14 with various liquid and gasfittings attached to it, which for the sake of clarity are notseparately numbered in FIG. 2.

FIG. 2 similarly illustrates a series of containers that correspond tothose shown schematically in FIG. 1. These include the solvent reservoirsupply 43, the starting material reservoirs 15 and 16, the productreservoir 37 and the waste reservoir 52. These all are respectivelyconnected to the multi-port valve 36 using the various fluid lines asdescribed in FIG. 1 and carrying the same reference numerals.

In FIG. 2 the peristaltic pump 17 is positioned within the upper housing19. Similarly, the multi-port valve 36 and the ball valve 34 areillustrated in FIG. 2 and carry the same reference numerals as FIG. 1.In the illustrated embodiment, the upper housing 19 carries severalvarious motors and (if necessary) associated gear or drive movementsthat drive the peristaltic pump 17, the ball valve and 34 and themulti-port valve 36.

FIG. 3 is an enlarged view of a portion of FIG. 2 that shows the top ofthe vessel 13 in more detail. In addition to showing the vessel 13 andthe pressure cap 14, FIG. 3 also illustrates a lock 56 and associatedsafety knob 57 that work in conjunction with a check valve 60 to preventunintended release of high pressure gases from the vessel 13. Inparticular, the lock 56 prevents the cap 14 from being removed from thevessel 13 until the safety knob 57 has been opened to allow pressure toescape through the check valve 60. In this manner, the lock 56 and theknob 57 prevent the lid 14 from being removed from the vessel 13 whenhigh pressures remain within the vessel 13.

FIG. 3 also shows the attenuator 61 on below the adapter plate 62. Anumber of the fluid and gas lines particularly 23 and 28 are alsoillustrated in the view of FIG. 3.

Although the operation of the instrument has been described in terms ofthe movement of individual samples, it will be understood that becausethe processor 26 is included and controls the valves, pump and relatedfluid flow, the instrument can be used in an automated fashion to carryout two or more identical or different reactions in sequence. The numberof reactions that can be carried at in sequence is not limited by theprocessor or the vessel, but primarily by the number and type ofreservoirs, fluid lines and valves that are included in any particularversion of the device. Thus, it will be understood that the processor 26can be programmed to carry out several reactions in sequence byselectively pumping specific starting materials from particularreservoirs at particular times to the reaction vessel and then exposingthose materials to microwave radiation.

Following any one particular reaction, the vessel 13, the various fluidlines, and the valves 34 and 36 can be rinsed if necessary or desiredwith solvent from the solvent reservoir 43. Rinsing is optional, ofcourse, and may not need to be carried out between all reactions, butthe instrument provides the opportunity to carry out rinsing in manualor automated fashion as may be desired.

In another aspect, the invention is a method of conducting microwaveassisted chemical reactions using high viscosity liquids orheterogeneous mixtures of liquids and solids. It will be understood thatalthough the invention (as both instrument and method) is best describedin terms of its capabilities of handling highly viscous liquids andheterogeneous mixtures, the invention is not limited to such materials,and homogeneous, free-flowing liquids (including compounds andsolutions) can be used as well.

In this aspect, the method comprises pumping a discrete portion of acomposition selected from the group consisting of high viscosity liquidsand heterogeneous mixtures of liquids and solids to a microwavetransparent pressure resistant reaction vessel at ambient pressures ofbetween about atmospheric pressure and about 30 psi. The discreteportion is then isolated in the pressure resistant vessel, followingwhich microwave radiation is applied to the isolated discrete portion inthe reaction vessel to initiate and maintain a chemical reaction at apressure of at least about 175 psi while preventing the vessel fromreleasing higher-pressure gases generated by a chemical reaction in thevessel. Pressure is next released from the vessel following desiredcompletion of the chemical reaction and the reaction products of thediscrete portion are pumped from the vessel at ambient pressures ofbetween about atmospheric pressure and about 30 psi following thepressure release.

In preferred embodiments, and incorporating additional aspects of theprocessor 26 illustrated in FIG. 1, the method comprises pumping asecond discrete portion after the first portion has been pumped out onthe reaction vessel and thereafter carrying out the steps of isolatingthe second portion, applying microwave radiation to the second portion,releasing pressure from the vessel, and pumping reaction products fromthe vessel.

As a particular advantage over those continuous flow instruments thatincorporate a length of tubing in the microwave field, the method canfurther comprise stirring the discrete portion in the reaction vesselduring the step of applying microwave radiation. For the sake of clarityFIG. 1 does not illustrate such a stirrer, but it will be understoodthat a very typical and exemplary technique is to include aTeflon-coated magnetic stirrer bar in the vessel and to rotate it usingan external magnet beneath or adjacent the vessel.

As noted previously, the step of applying microwave radiation preferablycomprises applying single or dual modes rather than multiple modes inthe cavity. Those familiar with microwave modes will recognize that theestablishment of a specific single or duel mode in a particular cavityis a function of the wavelength (frequency) of the microwaves and thedimensions, potentially including the shape, of the cavity into whichthe microwaves are propagated. Differently shaped cavities can beincorporated with different wavelengths to produce a single or dual-modeof radiation. In the present invention, the single mode cavities thatare described and set forth in the commonly assigned andpreviously-incorporated patents and applications are exemplary.

As set forth with respect to the structural aspects of the invention,the method can also comprise, and often typically comprises, maintainingtheir reaction vessel at a constant temperature for an extended portionsof a chemical reaction, recognizing of course that the reaction willneed to heat up to such temperature on as an initial part of thereaction scheme. The method also comprises measuring the temperature ofthe reaction vessel or of its contents, and then adjusting theapplication of microwave radiation in response to the measuredtemperature. The method also preferably comprises the step of measuringthe temperature of the reaction vessel or its contents and cooling thereaction vessel in response to the measure temperature so that thecombination of adjusting the applied or propagated microwave radiationand the application of cooling keeps the reaction subject to a desiredamount of microwave radiation but at a desired fixed temperature.

In preferred embodiments, the method comprises maintaining the pressurein the reaction vessel at between about 175 and 250 psi as this rangetends to be the temperature and pressure range at which a number ofchemical reactions proceed most favorably.

As described with respect to the structural elements of the invention,the method can also comprise rinsing or backwashing the reaction vesselwith a solvent between the steps of pumping the first reaction productsand pumping the second discrete portion. In preferred embodiments, themethod comprises driving the rinsing solvent with an inert gas. As usedherein the term “inert” does not necessarily (although it can) refer tothe noble gases, but includes any appropriate gas that does notdisadvantageously react with the instrument, the reactants, or theproducts. In many (but not necessarily all) applications nitrogen is anappropriate inert gas for these purposes.

Because the number of components (reactants, products, catalysts, solidsupports) is limited only by the selection valves and piping, the methodpreferably comprises mixing the composition to be pumped and exposed tomicrowaves from components selected from the group consisting of solids,liquids, solutions, solid phase catalysts and solid-supported reagentsprior to the step of pumping the composition to the reaction vessel.

In the drawings and specification there has been set forth a preferredembodiment of the invention, and although specific terms have beenemployed, they are used in a generic and descriptive sense only and notfor purposes of limitation, the scope of the invention being defined inthe claims.

1. A controlled-flow microwave instrument for chemical synthesis thatincludes heterogeneous or highly viscous materials, said instrumentcomprising a microwave source for generating electromagnetic radiationin the microwave frequencies; a microwave cavity in wave communicationwith said source for exposing compositions placed therein to microwaveradiation; means for adjusting microwave power applied from said sourceto said cavity; a microwave-transparent pressure resistant reactionvessel in said cavity; a source reservoir for starting materials andrelated compositions for the chemical synthesis reaction; a pumpselected from the group consisting of peristaltic pumps, diaphragmpumps, and pneumatic pumps in communication with said source reservoirfor pumping heterogeneous or highly viscous materials from said sourceto said reaction vessel; and a pressure-resistant valve between saidpump and said reaction vessel for isolating said reaction vessel fromsaid pump and said source during application of microwave energy tocompositions in said vessel and from any resulting high pressuresgenerated therein.
 2. An instrument according to claim 1 wherein saidcavity is selected from the group consisting of single mode and dualmode cavities.
 3. An instrument according to claim 1 comprising atemperature detector associated with said cavity for measuring thetemperature of items in said cavity.
 4. An instrument according to claim1 comprising a processor in operative communication with saidtemperature detector and said adjusting means for adjusting themicrowaves applied from the source to the cavity in response to thetemperature measured by said temperature detector.
 5. An instrumentaccording to claim 4 comprising means for cooling said vessel in saidcavity.
 6. An instrument according to claim 4 comprising means forcooling said vessel in said cavity during the application of microwaves.7. An instrument according to claim 5 wherein said cooling means is inoperative communication with said processor for operating said coolingmeans in response to the temperature measured by said temperaturedetector.
 8. An instrument according to claim 1 wherein said source isselected from the group consisting of magnetrons, klystrons and solidstate devices.
 9. An instrument according to claim 1 wherein saidpressure-resistant valve comprises a ball valve.
 10. An instrumentaccording to claim 9 wherein said ball valve is pressure resistant to atleast 175 psi.
 11. An instrument according to claim 9 wherein said ballvalve is pressure resistant to at least 250 psi.
 12. An instrumentaccording to claim 1 wherein said pressure-resistant reaction vessel hassufficient strength to maintain reactions therein at pressures of atleast about 175 pounds per square inch.
 13. An instrument according toclaim 1 wherein said pressure-resistant reaction vessel has sufficientstrength to maintain reactions therein at pressures of at least about250 pounds per square inch.
 14. An instrument according to claim 1wherein said pump is a two-way pump for adding materials to and pumpingmaterials from said reaction vessel, and said instrument furthercomprising: a multi-port valve between said source reservoir and saidpump for controlling the flow of materials to and from said reactionvessel; a second source reservoir for starting materials in fluidcommunication with said multi-port valve for providing said reactionvessel with a second set of starting materials; a product reservoir influid communication with said multi-port valve for collecting reactionproducts from said reaction vessel; and a processor in operativecommunication with said two-way pump and said multi-port valve fordirecting the flow of materials to and from said multi-port valve, saidtwo way pump, and said reaction cell.
 15. An instrument according toclaim 14 and further comprising: a plurality of fluid lines for provingfluid communication within said instrument; a solvent supply in fluidcommunication with said multi-port valve for providing solvent to saidreaction cell and for rinsing and cleaning said fluid lines; a vent influid communication with said multi-port valve for venting gases fromsaid reaction vessel; a waste reservoir in fluid communication with saidmulti-port valve for receiving waste product; and a gas supply in fluidcommunication with said multi-port valve and with said fluid lines forsupplying gas pressure to urge materials through said fluid lines.